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Gestational Trophoblastic Disease

Cecelia H. Boardman, M.D.Assistant Professor

Obstetrics and GynecologyVCU School of Medicine

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Gestational Trophoblastic Disease

GTD includes • Complete mole

• Partial mole

• Invasive mole

• Placental site trophoblastic tumor (PSTT)

• Choriocarcinoma

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Nomenclature

• A spectrum of disease

• Pathologic diagnosis

• In contrast to clinically significant diagnosis requiring active management

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Key Points

• Partial and complete mole are abnormal pregnancy events

• Choriocarcinoma is an aggressive malignancy akin to testicular cancer

• Partial and complete moles have the potential to persist, spread, and act like choriocarcinoma

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Key Points

• PSTT is generally an indolent malignancy that may be difficult to diagnose

• Treated aggressively, gestational trophoblastic malignancies are highly curable

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Key Points

• Benign conditions: partial mole, complete mole

• Malignant conditions: Invasive mole, persistent mole, PSTT, choriocarcinoma, metastatic GTD

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Epidemiology of Molar Pregnancy

• Molar pregnancy 7x more common in Asia– Taiwan: 1 in 125 pregnancies– US: 1 in 1500 live births

• More common in countries with low dietary carotene (vitamin A precursor) and animal fat

• Regions with high incidence of vitamin A deficiency have high rate of moles

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• Risk increases for complete mole with advanced maternal age

• Risk increases for complete mole with Hx SAb and infertility

• Risk for partial mole associated with HxOCP use and irregular menses

Epidemiology of Molar Pregnancy

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Immunobiology of GTD• Host immune response to paternal

antigens on trophoblast cells may contribute to curability

• Histocompatibility between patient and partner is associated with drug resistant choriocarcinoma and greater risk of metastatic GTD

• Prognosis of choriocarcinoma is related to the intensity of lymphocyte and monocyte infiltration at the tumor host interface 10

Molecular Pathogenesis of GTD

Complete mole and choriocarcinoma

• Overexpression of c-myc, c-erbB2, bcl-2

• Increased expression of p53, p21, Rb, and MdM2

• Modification of parental imprinting

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Pathology

Complete mole:• No fetal or embryonic tissue

• Diffuse trophoblastic hyperplasia

• Hydatidiform swelling of the chorionic villi

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Hydropic villi of complete mole

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Complete mole

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Trophoblastic proliferation of complete mole

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Invasive mole

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Chloriocarcinoma

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Pathology

Partial mole:• Identifiable embryonic or fetal tissue

• Focal trophoblastic hyperplasia +/- atypia

• Chorionic villi of varying size

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Partial mole

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Partial mole

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Partial mole

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Partial mole lacks circumfirentialtrophoblastic proliferation

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Complete Mole

Classic Clinical Presentation:• Vaginal bleeding • Theca lutein ovarian cysts

– Due to hyperstimulation from ↑↑ hCG• Size > dates • Classic snowstorm ultrasound picture• Hyperemesis

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Pelvic ultasound showing snowstorm pattern of complete mole

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Pelvic ultasound showing snowstorm pattern of complete mole

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Theca lutein cysts of both ovaries

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Complete Mole

Contemporary Clinical Presentation:• Vaginal bleeding

• Markedly elevated hCG

• Pathologic diagnosis

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Partial Mole

Classical Clinical Presentation• Second trimester preeclampsia

• IUGR fetus

Contemporary Clinical Presentation• Missed or incomplete Ab

• Diagnosis usually on histologic review

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Natural History

Complete mole• Present with markedly elevated ß-hCG

• Develop uterine invasion in 15%

• Develop distant metastasis in 4%

Partial mole• Persistent local disease develops in 0-11%

• Rarely develop metastatic disease

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Complete Mole

Issues with operative intervention:• Hemorrhage

• Uterine atony

• Dissemination of trophoblast

Management:• Two large bore IVs

• Pitocin in IV fluid on evacuation

• Attentive anesthesia30

Management of Molar Pregnancy

Evacuation• Assess for medical complications

– Anemia, hyperthyroidism, preeclampsia, electrolyte imbalances, respiratory insufficiency

• Mode: hysterectomy vs. suction curettage– Rhogam if Rh negative– Attentive anesthesia– Adequate IV access

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Management of Molar Pregnancy

Hormonal follow-up• weekly until normal for 3 weeks

• monthly for 6 months

• effective contraception

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Persistent GTD• Diagnosis: re-elevation or persistent plateau

hCG for at least 3 consecutive weeks • Risk increased with

– Complete mole– Markedly elevated hCG– Excessive uterine size– Theca lutein cysts– Repetitive molar pregnancy– Age > 40

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Persistent GTDHistology (Academic – DO NOT BIOPSY)• following molar pregnancy: molar tissue or

choriocarcinoma• following a nonmolar gestation:

choriocarcinoma• choriocarcinoma: sheets of anaplastic cyto-

and syncytiotrophoblast (no villi)• PSTT: mononuclear intermediate trophoblast

(no villi• NB: choriocarcinoma can rarely involve the

fetus 36

Complete Mole

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Choriocarcinoma

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Persistent GTD

The confusion:• Can be local or metastatic

• Can be low or high risk– Treatment is based on risk, not stage

• Can follow any type of conception event

• Has a variety of names….

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Nonmetastatic GTD

Nonmetastatic disease• Develops in 15% after a complete mole

• Rare following other gestations

• May present with vaginal or intraperitonealbleeding or uterine infection

• May also present with irregular vaginal bleeding, ovarian cysts, persistently elevated hCG

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Metastatic GTD

Metastatic disease• Develops in 4% after a complete mole

• Rare following other gestations

• Often associated with choriocarcinoma

• Fragile tumor vessels lead to hemorrhagic metastases

• Propensity for early vascular invasion with widespread dissemination

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Metastatic GTD

Presentation of metastatic disease:• Hemoptysis• Acute neurologic deficits• Unexplained systemic symptoms• Unexplained pulmonary symptoms

Always check an hCG in a woman of reproductive potential with unusual symptoms-- metastatic GTD is often overlooked! 42

Metastatic GTD

Most common metastatic sites:• Lung - 80%• Vagina - 30%• Brain - 10%• Liver - 10%

Biopsy is not required -- only radiographic confirmation with an elevated hCG

DO NOT BIOPSY! BEWARE BLEEDING!

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Metastatic GTD

Lung metastases presentations:• Asymptomatic• Dyspnea• Chest pain• Cough• Hemoptysis• Right heart strain and pulmonary

hypertension

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Metastatic GTD

Lung metastases patterns on CXR:• Pleural effusion

• Alveolar or snowstorm pattern

• Discrete round densities

• Embolic pattern caused by pulmonary arterial occlusion by tumor

• i.e. Anything goes!!!

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AP Chest x-ray with large right lower lobe metastasis from GTD

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Lateral view, same patient

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AP Chest x-ray with right middle lobe metastasis from GTD (arrow)

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AP Chest x-ray with alveolar pattern from metastasis from GTD

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Metastatic GTD

Lung metastases • Beware respiratory failure

• Risk factors:– >50% lung opacification

– dyspnea

– cyanosis

– anemia

– pulmonary hypertension

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Metastatic GTD

Vaginal metastases • Presentation:

– irregular bleeding

– purulent discharge

• Location– fornices

– suburethrally

• DO NOT BIOPSY!!!!!!!!! (particularly if you are wearing your favorite shoes…)

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Cystic anterior vaginal wall metastasis from GTD

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Metastatic GTD

Brain metastases presentation:• Vomiting• Seizures• Headache• Hemiparesis• Slurred speech• Visual disturbances

Symptoms result from increased intracranial pressure or intracerebralbleeding

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Metastatic GTD Management

Cerebral metastasis• whole brain radiation plus chemotherapy

– reduces mortality• systemic plus intrathecal chemotherapy• craniotomy for herniation or control of bleeding

– may also resect resistant tumors• these patients can be cured!

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Metastatic GTD

Liver metastases presentation:• Jaundice

• Intra-abdominal bleeding

• Epigastric pain

Isolated liver metastasis are rare -- patient presentation is usually due to mets to other sites

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Metastatic GTD

Case Scenario47 yo Latina presents to ERCC: SOBBP: 170/90CXR: CHFhCG: 2,000,000

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Metastatic GTD

Case Scenario22 yo Latina presents to clinic for

evaluationCC: plateaued hCG following molar

pregnancyPE: nonfocalChest CT: 40 subcentimeter metastasis

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Metastatic GTD

Case Scenario25 yo Caucasian female with 15 mo child

lifeflighted to academic medical center with decreased LOC

Head CT: Hemorrhagic temporal lobe lesion (4 cm) with midline shift

Abdominal CT: 4 cm liver lesion

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Metastatic GTD

Case Scenario27 yo Caucasian female status post SAb

presents with abnormal uterine bleedinghCG + Given MTXT x 1hCG persistently positiveUS reveals hypervascular 5 cm

intrauterine mass

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Metastatic GTD

Take home message:All GTD needs thorough evaluation for

metastatic diseaseEvaluation must be expeditiousDO NOT BIOPSY ANYTHING!!!!!!!

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Metastatic GTDStaging:

• FIGO anatomic staging system– Stage does not always correlate with

prognosis…..

– Generally, Stage I is low risk and Stage IV is high risk

• WHO prognostic scoring system– Predicts responsiveness to chemotherapy

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Metastatic GTDFIGO anatomic staging system:• Stage I: confined to the uterus

• Stage II: extension to genital structures (vagina, adnexa, broad ligament)

• Stage III: lung metastases

• Stage IV: all other metastatic sites

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Metastatic GTDFIGO anatomic staging system:

• Substages:– A: no risk factors

– B: one risk factor

– C: two risk factors

• Risk factors:– hCG > 100,000

– > 6 months since antecedent pregnancy

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Metastatic GTDWHO prognostic scoring system• Points assigned based on certain clinical

variables

• Allows appropriate selection of chemotherapy

• Low risk: score < 4

• Intermediate risk: score 5-7

• High risk: score > 8

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Metastatic GTDWHO prognostic scoring system variables• Time since and type of antecedent pregnancy• Blood group• hCG level• Location of mets; size of largest met• Number of mets• Prior chemo drugs• Age

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Metastatic GTDDiagnostic Evaluation• History and Physical

• hCG levels

• labs: TFTs, LFTs, renal function, CBC

• CXR

• if vaginal/lung mets and/or choriocarcinoma, CT or MRI head, abdomen, and pelvis– rare to have brain or liver mets if pelvic exam

and CXR normal66

GTD ManagementDepends on• Stage of disease

• Risk factors (WHO score)

• Desire for future fertility

• Ability to be compliant

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GTD ManagementSurgery• Hysterectomy if:

– patients have completed childbearing – locally persistent disease– PSTT (relatively chemo resistant)– control uterine hemorrhage or sepsis– resect bulky tumor to decrease need for chemo

• Uterine wedge resection• Thoracotomy• Liver wedge resection to control hemorrhage• Neurosurgery 68

GTD ManagementChemotherapy• Single agent: actinomycin D or methotrexate

– For low risk/low stage patients– Even with Stage II/III patients, low risk,

response rates are 84-87%

• Combination: EMACO vs MAC vs EMA– For high risk and Stage IV patients

• Treat two-three cycles beyond negative hCG(best done by a gyn onc)

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Metastatic GTD ManagementLaboratory follow-up• Stage I/II/III:

– hCG weekly until normal x 3 then monthly x 12– contraception x 12 months

• Stage IV:– weekly hCG until normal x 3 then monthly x 24– increased risk of late recurrence– Contraception x 24 months

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Metastatic GTD ManagementRelapse• Risk: 2% with nonmetastatic disease

– 4% with low risk metastatic disease

– 13% with high risk metastatic disease

– Stage I - 3%, Stage II - 8%, Stage III - 4%, and Stage IV - 9%

• Recurrence within 3 months in 50% and 18 months in 85%

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Metastatic GTD ManagementRelapse• Stage I-III patients usually salvaged

• Stage IV patients usually die

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GTD ManagementSubsequent pregnancies• Complete mole - normal reproductive future• Partial mole - reassuring data• After two molar pregnancies, recurrence risk is

15-23%• Therefore, 1st trimester US in subsequent

pregnancy is not unreasonable• Also, pathologic evaluation of the placenta and

6 wk pp hCG levels

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GTD ManagementSubsequent pregnancies• After GTD, similarly normal pregnancy

outcomes

• Similar management recommendations

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Metastatic GTD ManagementhCG Assays• hCG molecules in GTD can be more degraded

and/or heterogenous-- assay needs to detect intact hCG as well as metabolites and fragments– hence, “tumor beta”

• cross-reactivity with LH– prevent menopausal rise of LH in 30-40 yo with

OCPs during chemo

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Gestational Trophoblastic Disease Summary• Keep it simple, don’t get confused by

terminology

• hCG levels must plateau or rise over three weeks for a diagnosis of GTD

• Initial evaluation with physical exam and CXR

• I honestly do a total body CT

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Gestational Trophoblastic DiseaseSummary• Disease can progress rapidly-- metastatic

survey must be done ASAP (ADMIT!)

• WHO scoring system more predictive of poor outcome that FIGO staging

• Single agent methotrexate and actinomycin-D are very effective in low-risk disease

• EMA-CO is the most effective combination regimen for high-risk disease

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Gestational Trophoblastic DiseaseSummary• Even patients with brain mets/Stage IV disease

can be cured– Think Lance Armstrong !

• These women need aggressive expeditious management

• Women with GTD are best managed by a gynecologic oncologist with experience in GTD

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Gestational Trophoblastic Disease

Cecelia H. Boardman, M.D.Assistant Professor

Obstetrics and GynecologyVCU School of Medicine